Parsing the Roles of the Transcription Factors GATA-4 and GATA-6 in the Adult Cardiac Hypertrophic Response

The transcriptional code that programs cardiac hypertrophy involves the zinc finger-containing DNA binding factors GATA-4 and GATA-6, both of which are required to mount a hypertrophic response of the adult heart. Here we performed conditional gene deletion of Gata4 or Gata6 in the mouse heart in conjunction with reciprocal gene replacement using a transgene encoding either GATA-4 or GATA-6 in the heart as a means of parsing dosage effects of GATA-4 and GATA-6 versus unique functional roles. We determined that GATA-4 and GATA-6 play a redundant and dosage-sensitive role in programming the hypertrophic growth response of the heart following pressure overload stimulation. However, non-redundant functions were identified in allowing the heart to compensate and resist heart failure after pressure overload stimulation, as neither Gata4 nor Gata6 deletion was fully rescued by expression of the reciprocal transgene. For example, only Gata4 heart-specific deletion blocked the neoangiogenic response to pressure overload stimulation. Gene expression profiling from hearts of these gene-deleted mice showed both overlapping and unique transcriptional codes, which is presented. These results indicate that GATA-4 and GATA-6 play a dosage-dependent and redundant role in programming cardiac hypertrophy, but that each has a more complex role in maintaining cardiac homeostasis and resistance to heart failure following injury that cannot be compensated by the other.